An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems
Abstract
:1. Introduction
2. Anatomical and Physiological Features of the Oral Cavity
2.1. Permeability
2.2. Oral Environment
3. Drug Transport Mechanisms
4. Design and Formulation of Buccal Drug-Delivery Systems
4.1. Mucoadhesive Polymers
4.2. Penetration Enhancers
4.3. Enzyme Inhibitors
5. Buccal Patch
6. Buccal Film
7. Functional Role of Nanoparticles in Buccal Drug-Delivery Systems
7.1. Polymeric Nanoparticles
7.2. Lipid Nanoparticles
7.2.1. Liposomes
7.2.2. Solid-Lipid Nanoparticles
7.2.3. Nanostructured Lipid Carriers (NLCs)
7.3. Nanosuspensions
8. In Vitro Evaluation Techniques
9. Preparation Methods, Scale-Up Process and Manufacturing Considerations
10. Clinical Translation of Buccal Administered Molecules
11. Future Perspectives and Directions
12. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Category | Examples | Transport Mechanism | Key Findings | References |
---|---|---|---|---|
Surfactants | Anionic: Sodium lauryl sulfate, sodium dodecanoate Cationic: Cetylpyridinium chloride | Disruption of intercellular lipids and integrity of protein Increase water solubility of drugs | Mucosal lipids might be extracted above critical micelle concentration therefore reducing the barrier properties of buccal mucosa | [58,59,60,61] |
Non-ionic: Polyoxyethylene-9-lauryl ether, nonylphenoxy poly oxyethylene, polysorbates (Tweens), sorbitan fatty acid esters (Spans), macrogol ethers (Brijs), macrogol esters (Myrjs) | Hydrophobic interaction between surfactant and keratin fibrils causes swelling of epithelium | |||
Bile salts: Sodium taurocholate, sodium cholate, sodium deoxycholate, sodium taurodihydrofusidate, sodium taurodeoxycholate | Penetration into intercellular regions, increase fluidity, solubilization and extraction of lipids Interaction with keratin leads to disruption of corneocytes | |||
Fatty acids and their esters | Capric acid, caprylic acid, lauric acid, linoleic acid, linolenic acid, oleic acid, 2-octyldodecyl myristate, 1-[(N,N-dimethylamino)propan-2-yl]dodecanoate) | Interact with phospholipid domain and increase the membrane fluidity | A parabolic correlation observed between fatty acid lipophilicity and permeation enhancement Ability to diffuse through mucosa and interact with the lipid region is determined by fatty acid chain length Improve paracellular bioabsorption through transient opening of tight junctions | [62,63] |
Cyclodextrins | α,β,γ cyclodextrins, methylated cyclodextrins | Disruption of intercellular lipids and integrity of protein | Molecular inclusion complex resulting in solubilization, lipid extraction and increasing buccal absorption | [64] |
Polymers | Cationic: Chitosan, trimethyl chitosan, poly-L-arginine, L-lysine | Ionic interaction with negatively charged carboxyl and sulfate groups on mucin | Enhancement effect may be due to increasing the retention of the drug at the mucosal surface, which decrease the clearance of the drug by salivary flow Cationic cell penetrating peptide permit its interaction with anionic motifs on the mucin by a receptor-independent mechanism thus overcoming cell membrane impermeability and cellular internalization of actives | [65] |
Chelating agents | Ethylenediaminetetraacetic acid, polyacrylate, citric acid, salicylates | The chelators form complexes with Ca2+ ions | Probably widen the gap between the cells and consequently facilitate paracellular transport of particularly, hydrophilic drugs | [66] |
Miscellaneous | Azone (1-dodecylazacycloheptan-2-one) | Disrupts the lipid bilayers and increases the fluidity and permeation in the lipid regions of the biological barrier | Efficacy strongly dependent on its concentration (1–5%) and is also influenced by the choice of vehicle from which it is applied Effective for both hydrophilic and lipophilic drugs in polar medium | [67] |
Type | Polymer Constituents | Drugs Used | Manufacturing Method | Highlights | References |
---|---|---|---|---|---|
Controlled release | Carbopol, hydroxypropyl methylcellulose (HPMC), poloxamer and compritol 888 ATO | Lidocaine | Solvent casting | Free lidocaine and/or microspheres loaded patch fabricated using HPMC/carbopol and poloxamer Lidocaine microspheres prepared from Compritol 888 ATO employing spray congealing technique Change in formulation composition demonstrated to change the drug release mechanisms and able to provide either rapid, delayed or prolonged local anesthetic activity | [83] |
Sustained release | Sodium alginate, HPMC, sodium carboxymethyl cellulose (NaCMC) and carbopol | Atenolol | Solvent casting | Patch prepared from sodium alginate Ex vivo permeation studies across goat buccal mucosa revealed 70.17 ± 2.28% release over a period of 24 h with maximum permeation flux (30.83 ± 1.23 μg/cm2/h) and minimum lag time (0.95 ± 0.22 h) Polymers used could provide sustained release of atenolol across porcine buccal mucosa for 24 h | [84] |
Modified release | Xanthan gum, polyvinyl alcohol (PVA) and HPMC E-15 | Zolmitriptan | Solvent casting | Bilayer patch prepared from xanthan gum In vitro drug release studies showed rapid drug release; 43.15% within 15 min, followed by sustained release rate over 5 h Incorporation of 4% dimethyl sulfoxide demonstrated 3.29-fold drug permeation, transported 29.10% of drug after 5 h | [85] |
Immediate release | HPMC, PVA, polyvinylpyrrolidone and ethyl cellulose | Carbamazepine | Solvent casting | Water impermeable polypropylene backing layer provided unidirectional drug release Due to high water uptake, PEG 400 containing batches showed maximum in vitro release and increased mucoadhesion Drug release was controlled by either diffusion or non-Fickian diffusion | [86] |
Peptide delivery | Chitosan, choline and geranic acid | Insulin | Solvent casting | Viscous gel made of choline and geranic acid sandwiched between two layers of chitosan Significant increase (7-fold) in the cumulative insulin transport across the ex vivo porcine buccal tissue was demonstrated (~26% of loaded insulin) In vivo studies in rat buccal pouch lowered blood glucose levels up to 50% in a dose dependent manner Serum insulin plateaued after 3 h for the duration of the study | [87] |
Therapeutic Classification | Polymer/Plasticizer | Active Ingredient | Manufacturing Method | Comments | References |
---|---|---|---|---|---|
Antihypertensive | Chitosan, polyvinylpyrrolidone, PVA, gelatin/propylene glycol | Propranolol HCl | Solvent casting | Personalized bilayered buccal film useful for pediatric population | [95] |
Antifungal | Dextran, maltodextrin, HPMC, HPC/PEG 400 and glycerol | Amphotericin B | Solvent casting | Mechanical strength of the film was contributed by Avicel 200 and Avicel CL611 Physically stable orodispersible film was effective in oropharyngeal candidiasis | [96] |
Antiepileptic | HPMC | Diazepam | * | Soluble film formulation of diazepam (Libervant™) effective in acute seizure emergencies Dose can be adjusted by cutting the film of suitable size | [97] |
Antiprotozoal/anti-inflammatory | HPMC, PVA, chitosan/glycerin | Ornidazole and dexamethasone sodium phosphate | Solvent casting | Double layered film demonstrated >95% drug release in 4 h Significant effect on mucosal repair and reduced ulcer inflammation | [98] |
Anesthetic/analgesic and anti-inflammatory/ mucolytic | HPMC, NaCMC, Chitosan/propylene glycol and sorbitol | Lidocaine HCl, benzydamine HCl, N-acetyl-cysteine | Solvent casting | Biocompatible bilayered mucoadhesive film stimulates cell proliferation and demonstrated therapeutic effect in buccal mucositis | [99] |
Anti-inflammatory | HPMC, ethyl cellulose, chitosan, NaCMC, carbopol 971P/propylene glycol, PEG 8000 | Fluticasone propionate | Solvent casting | Optimized formulation exhibited sustained drug release for 10 h Enhanced pharmacokinetic parameters was demonstrated compared to equivalent dose of mouthwash | [100] |
Types of Nanoparticles | Nanoparticle Composition | Method | Polymers/Drug | Outcome | Key Points | References |
---|---|---|---|---|---|---|
Nanospheres | Poly (lactic-co-glycolic acid) | Double-emulsion solvent evaporation | HPMC K15 and Eudragit RS 100/selegiline | Potential to prolong retention, provide controlled release, enhance bioavailability | Buccal film fabricated from HPMC and eudragit embedded with poly (lac-tic-co-glycolic acid) nanospheres Permeation rate of selegiline mainly influenced by the film composition used The overall mean value of AUC0-α (2935.65 ± 194.24 ng.h/mL) from buccal film was found to be ~3 fold higher (p < 0.0001) as compared to oral solution | [124] |
Nanoparticles | Poly (lactic-co-glycolic acid) | Double-emulsion solvent evaporation | Chitosan/ C-glycosyl flavonoid fraction of Cecropia glaziovii | Capacity to overcome low bioavailability of flavonoid extract | Dynamic mechanical analysis tests indicated that increasing of nanoparticles concentration caused decreased stiffness and an increased glass transition temperature Cytotoxic assay results indicated that these systems showed no cytotoxicity | [125] |
Solid-lipid nanoparticles | Lipoid S100 and polysorbate 80 | Solvent injection | HPMC/coumarin 6 | Could be used for poorly aqueous soluble drugs | Lipid nanoparticles improved the cellular permeability through mucosal epithelial cells The quality of the solid-lipid nanoparticles loaded film and placebo mucoadhesive film were same | [126] |
Liposomes | Polyvinylpyrrolidone | Electron spinning | Na CMC and chitosan/carvedilol | Initial burst release avoided with positive effect on permeation | Coaxial fibers-based self-assembling liposomes formed Demonstrated significant permeation across porcine TR146 cell culture and porcine buccal mucosa Cytotoxicity assay indicated absence of any toxicity caused by the fibers | [127] |
Nanolipid structures | D-α-tocopherol PEG 1000 succinate, almond oil, compritol, phosphatidylcholine, gelucire 44/14 | Hot emulsification–ultrasonication technique | Carbopol 934 and HPMC/glimepiride | Suitability to transport across buccal mucosa in sustained release manner | Selected concentration of micelles to nanostructured lipid carriers, carbopol and sodium cholate were 100%, 0.05% and 1.8%, respectively using a Box-Behnken design Optimized mucoadhesive film with a backing layer of ethyl cellulose demonstrated unidirectional glimepiride release of 93.9% at 6 h | [128] |
Technique | Principle | Evaluation Parameters | Ranges Units | References |
---|---|---|---|---|
Tensile test | The resistance of the thin strip of film against a dragging force is determined using a texture analyzer or modified balance method. Young modulus measures the deformation tendency of the film | Tensile strength = breaking force (N)/cross-sectional area (cm2) of the film The slope value from stress strain curve measures the Young modulus Percentage at the break, strain energy, energy to break can be calculated | 16.6–24.3 MPa | [169,172] |
Puncture test | The resistance of the thin film against the compression force until it breaks, cracks, or a desired loss in the force resisting the probe movement occurs | Toughness | 0.2–13 mJ | [173,174] |
Indentation test | Measure load as a function of penetration depth | Hardness and elastic modulus | 1 mPa and ~100 mPa | [175] |
Folding endurance | Repeatedly fold the film at 180° angle of the plane at the same plane until it breaks or folded to 300 times without breaking. The number of times the film is folded without breaking is computed as the folding endurance value | Flexibility | ~300 count | [176] |
Water absorption capacity | Swelling capacity assess bioadhesion behavior and drug release from the film | Percentage hydration is calculated by the equation [(W2 − W1) × 100/W1], where W1 weight of the film, W2 weight of the film after swelling in simulated saliva after predetermined time | 5–25% | [177] |
Thickness and weight variation | Thickness is determined using electronic digital micrometer, screw gauge, vernier caliper or by scanning electron microscopy images. Weight variation is calculated by subtracting weight of individual film from average weight and then divided by average weight of the film | Uniformity of the dose in the film | 50–1000 μm and <50 mg | [169] |
Surface morphology | Fixing the films on stubs, sputter coated with gold in an inert environment and imaged | Surface texture, pores, crystallinity, uniformity of drug distribution, thickness | - | [178] |
Surface pH | Allowing it to swell by contact with distilled water for a short time (<2 h) at room temperature (25 °C) | pH at the area of application | 6.0–7.5 | [179] |
Crystallinity | Place the sample in the sample holder of X-ray diffractometer and scan | Presence of crystalline or amorphous form of the sample | % | [180] |
Thermal analysis | Heating the sample in aluminum pan at elevated temperature at uniform heating rate | Identify the existence of phase transition, recrystallization or molecular interaction of drug within the film | °C | [181] |
Fourier-transform infrared spectroscopy | Specific ratio of drug and potassium bromide compressed at particular pressure and scanned | Drug-polymer interaction | cm−1 | [182] |
Mucoadhesive strength | Buccal film is attached to the probe of the texture analyzer using cyanoacrylate adhesive. Buccal epithelium of rabbit is fixed on the stationary platform of a texture analyzer. The probe of the texture analyzer was brought down gradually till the probe touch the mucosa | Adhesion strength is evaluated using shear stress, peel strength and tensile strength depending on the direction in which the mucoadhesive material is detached from the biological surface | 6–7 N | [183] |
In vitro drug release | Paddle over disc method using USPXXIV Type 2 apparatus | Release of drug from the prepared film using simulated saliva (pH 6.2) | % | [184] |
Ex vivo permeation | Freshly excised buccal mucosa of rabbit using Franz diffusion cell, continuous flow diffusion cell, Ussing chamber, human buccal cell line (TR146), cell culture model | Establishing the absorption of drug across buccal epithelium by means of flux (J) and permeability coefficient (P) | J = μg/cm2/h P = cm/h | [17,181,185] |
Clinical Trials | Indication | Phase | Enrolment | Identifier |
---|---|---|---|---|
Buccal prochlorperazine (6 mg) plus 2 cc normal saline versus intravenous prochlorperazine (10 mg) 2 cc plus two saccharin absorbable placebo tablets | Migraine disorders | Phase III | 80 | NCT02779959 |
Diazepam buccal film (10 mg–17.5 mg based on body weight) administered on inner aspect of the following a low or high fatty meal versus diastat rectal gel (10 mg–20 mg based on body weight) following a moderate fatty meal | Epilepsy | Phase I and Phase II | 31 | NCT03953820 |
Palonosetron hydrochloride buccal film (0.25 mg and 0.5 mg) versus palonosetron hydrochloride, 0.25 mg/5 mL intravenous solution | Nausea with vomiting chemotherapy-induced | Phase II | 22 | NCT04592198 |
Montelukast buccal film, administered 10 mg once or 30 mg twice daily versus placebo buccal film administered once or twice daily | Alzheimer’s disease | Phase II | 70 | NCT03402503 |
A comparison of sublingual and buccal misoprostol regimens after mifepristone for mid-trimester abortion | Legally induced abortion | Phase IV | 320 | NCT02708446 |
Pharmacokinetic and pharmacodynamic study of three different doses (0.5 µg/kg, 0.75 µg/kg, and 1 µg/kg) of oral transmucosal dexmedetomidine | Sedation | Phase II and Phase III | 36 | NCT03120247 |
Single dose crossover study to compare the respiratory drive after administration of belbuca (300 μg, 600 μg and 900 μg), oxycodone (30 mg and 60 mg) and placebo | Respiratory depression | Phase 1 | 19 | NCT03996694 |
Safety and efficacy study of NH004 films (intra oral) with tropicamide at different dose (0.3 mg,1 mg and 3 mg) for relief of sialorrhea symptoms in Parkinson’s disease patients versus placebo | Sialorrhea in Parkinson’s disease | Phase II | 19 | NCT00761137 |
A double-blind, placebo-controlled evaluation of the efficacy, safety and tolerability of BEMA™ fentanyl (bioerodible mucoadhesive soluble fentanyl citrate film) in the treatment of breakthrough pain in cancer subjects | Breakthrough pain in cancer | Phase III | 152 | NCT00293033 |
Long-term open-label safety study to evaluate EN3409 (BEMA® Buprenorphine buccal film) at doses 300–900 μg | Low back pain, osteoarthritis, neuropathic pain | Phase III | 303 | NCT01755546 |
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Jacob, S.; Nair, A.B.; Boddu, S.H.S.; Gorain, B.; Sreeharsha, N.; Shah, J. An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems. Pharmaceutics 2021, 13, 1206. https://doi.org/10.3390/pharmaceutics13081206
Jacob S, Nair AB, Boddu SHS, Gorain B, Sreeharsha N, Shah J. An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems. Pharmaceutics. 2021; 13(8):1206. https://doi.org/10.3390/pharmaceutics13081206
Chicago/Turabian StyleJacob, Shery, Anroop B. Nair, Sai H. S. Boddu, Bapi Gorain, Nagaraja Sreeharsha, and Jigar Shah. 2021. "An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems" Pharmaceutics 13, no. 8: 1206. https://doi.org/10.3390/pharmaceutics13081206
APA StyleJacob, S., Nair, A. B., Boddu, S. H. S., Gorain, B., Sreeharsha, N., & Shah, J. (2021). An Updated Overview of the Emerging Role of Patch and Film-Based Buccal Delivery Systems. Pharmaceutics, 13(8), 1206. https://doi.org/10.3390/pharmaceutics13081206